This proposal will look to use novel natural products for the study and treatment of pain, depression, anxiety, and comorbid instances of pain and affective disturbances. Recent evidence demonstrates a significant interaction between chronic pain and psychiatric illness. In particular, chronic pain (e.g. fibromyalgia, chronic lower back pain, painful bladder syndrome) seems to be linked both epidemiologically and biologically with major depressive disorder (MDD). Rates of MDD or depressive/anxiety symptoms in chronic pain patients are very high. In this situation, the two separate diseases actually potentiate one another to create an acutely dangerous pathological environment. Interestingly, this overlap presents an important new mechanistic and therapeutic avenue for the treatment of patients. That is, these common mechanisms might be useful for the development of treatments that show efficacy against both diseases with a single agent. This scenario would be doubly advantageous in that it could be used as a prophylactic treatment in the early stages of a single disorder to prevent the development of the secondary disease (i.e. pain or depression). We aim to test the hypothesis that the common mechanisms of pain and depression can be used to target these disorders with novel compounds directed at serotonin G-protein coupled receptors (GPCRs). Serotonin is a brain neurochemical and serotonin receptors are one of the most common targets in psychiatric disease and more recently in chronic pain disorders. Most studies using serotonin-targeting agents, however, have used established drugs that were originally screened as either antidepressive OR analgesic agents, not both. We aim to improve the likelihood of success of our compounds by testing them for comorbid chronic pain and depression/anxiety during the initial testing. We will be testing extracts, fractions, and purified compounds from marine cyanobacteria previously collected in the highly biodiverse waters of Panama. The discovery of natural products from the marine environment is a fairly recent field of research but has yielded a large number of interesting and important compounds in a variety of disease areas. Predominately studies have focused on the discovery of toxic compounds for their utility as anti-bacterial, anti-fungal, or anti-cancer agents. This proposal, however, will examine extracts from marine cyanobacteria for their ability to modulate serotonin GPCRs, to treat pain and depression, using in vivo mouse models following initial screening of the extracts against GPCRs.